The A2ALL study group was established with the aim to understand the physiological and psychosocial impact of living donor transplantation (LDLT) on the donor, explore methods to assure donor safety and outcomes, to study outcomes in the recipient, and to apply innovative mechanistic methods to better understand the processes of liver regeneration and immunobiology that are pertinent to this setting. The scientific explorations from the A2ALL consortium have resulted in significant contributions that have advanced our understanding of the procedure, established important guidelines for donor and recipient selection, and compiled pertinent information for a more informed decision. The aims of this application are to demonstrate our commitment to the ongoing A2ALL studies, describe established procedures to assure collection of prospective data that is the core mission of the A2ALL consortium, and propose scientific studies that will enhance our understanding of biological responses that are critical for the recovery and long term well being of the donor and recipient. Our concept proposals aim to investigate molecular pathways of regeneration that impact donor and recipient liver function and patterns of alloimmune response in LDLT recipients. 1. Donor Concept Proposal: This proposal will seek to identify molecular patterns of recovery in the donor liver remnant and peripheral blood that are indicative of, and predict, the eventual return of liver function and mass. This will be accomplished by correlating gene expression in the remnant lobe and in sequential peripheral blood mRNA profiles, with longitudinal assessment of donor liver regeneration and quantitative liver function testing. 2. Recipient Concept Proposal: Using a randomized clinical trial design, this proposal will investigate whether LDLT facilitates safe minimization of immunosuppression. In a parallel mechanistic study, we will investigate whether peripheral blood cell mRNA profiles offer a noninvasive means of predicting and diagnosing LDLT allograft rejection. The goals laid out in this proposal can be met within the time frame for the extension of A2ALL and take advantage of the existing clinical database, stored donor and recipient specimens that can be used for molecular analysis, and include in the prospective interventional studies recipients that are already enrolled in A2ALL and are eligible and willing to participate in immunosuppression minimization study. PUBLIC HEALTH RELEVANCE: As outcomes improve and more benefits are recognized, there is increased interest in living donor transplantation. Before significant expansion can occur, it is important to determine the consequences of the living donor procedure with regard to donor well-being and recipient outcomes. Potential interventions to improve liver function and regeneration in the donor, and efforts to prolong graft function and minimize side effects of immunosuppression in the recipient can have great impact on long-term outcomes.